Multi-conjugates comprising a mono-substituted homo-bivalent linker

Abstract

Various embodiments provide a homo-bivalent covalent linker substituted on one end by a substituent X, wherein X comprises a biological moiety other than a nucleic acid.

1 . A compound comprising a homo-bivalent covalent linker substituted on one end by a substituent X, wherein X comprises a biological moiety other than a nucleic acid, wherein the other end of the homo-bivalent linker is unsubstituted, and wherein the compound is at least 75% pure. 
     
     
         2 . The compound of  claim 1 , wherein the compound comprises Structure 1:
   X—R1-R2-A-R3-B  (Structure 1)
   wherein:   X is a substituent comprising a biological moiety other than a nucleic acid;   R1 is a group comprising phosphodiester, thiophosphodiester, sulfate, amide, triazole, heteroaryl, ester, ether, thioether, disulfide, thiopropionate, acetal, glycol, or is absent;   R2 is a spacer group, or is absent;   A is a group comprising the reaction product of a first nucleophile and a first electrophile;   R3 is a group comprising a C 2 -C 10  alkyl, C 2 -C 10  alkoxy, C 1 -C 10  aryl, C 2 -C 10  alkyldithio, amide, ether, thioether, ester, oligonucleotide, oligopeptide, thiopropionate, or disulfide; and   B is a group comprising a second nucleophile or a second electrophile, wherein the second nucleophile is the same as the first nucleophile, and the second electrophile is the same as the first electrophile.   
     
     
         3 . The compound of  claim 2 , wherein R2 comprises a C 2 -C 10  alkyl, C 2 -C 10  alkoxy, or C 1 -C 10  aryl, or is absent. 
     
     
         4 . The compound of  claim 2 , wherein the first nucleophile and first electrophile of A comprise (i) a thiol and a maleimide, optionally wherein the reaction product of the thiol and maleimide is a derivative of succinamic acid; (ii) a thiol and a vinylsulfone; (iii) a thiol and a pyridyldisulfide; (iv) a thiol and an iodoacetamide; (v) a thiol and an acrylate; (vi) an azide and an alkyne; or (vii) an amine and a carboxyl. 
     
     
         5 . The compound of  claim 4 , wherein A is a group comprising the reaction product of a thiol and a maleimide, optionally wherein the reaction product of the thiol and maleimide is a derivative of succinamic acid. 
     
     
         6 . The compound of  claim 2 , wherein R3 is a group comprising a thiopropionate or disulfide, an oligonucleotide, or an oligopeptide. 
     
     
         7 . The compound of  claim 2 , wherein the compound comprises Structure 2 or a pyrrolidinedione ring-opened derivative thereof, optionally wherein the pyrrolidinedione ring-opened derivative of Structure 2 is a derivative of succinamic acid: 
       
         
           
           
               
               
           
         
       
     
     
         8 . The compound of  claim 7 , wherein R2 is a spacer group comprising a C 2 -C 10  alkyl, C 2 -C 10  alkoxy, or C 1 -C 10  aryl. 
     
     
         9 . The compound of  claim 7 , wherein:
 X is a peptide or protein, or a derivative thereof;   R1 and R2 are absent; and   R3 is a group comprising a thiopropionate, disulfide, or oligonucleotide.   
     
     
         10 . The compound of  claim 7 , wherein:
 X is an organometallic compound, or a derivative thereof;   R1 is an ester group;   R2 is a spacer group comprising a C 2 -C 10  alkyl; and   R3 is a group comprising a thiopropionate, a disulfide, an oligonucleotide, or an oligopeptide.   
     
     
         11 . The compound of  claim 7 , wherein:
 X is a small molecule, or a derivative thereof;   R1 is an ester group;   R2 is a spacer group comprising a C 2 -C 10  alkyl; and   R3 is a group comprising a thiopropionate, a disulfide, an oligonucleotide, or an oligopeptide.   
     
     
         12 . The compound of  claim 1 , wherein the homo-bivalent covalent linker comprises a linker that is cleavable under intracellular conditions. 
     
     
         13 . The compound of  claim 2 , wherein the R3 group comprises a linker that is cleavable under intracellular conditions. 
     
     
         14 . The compound of  claim 2 , wherein the substituent X is a peptide, protein, lipid, carbohydrate, carboxylic acid, vitamin, steroid, lignin, small molecule, organometallic compound, or a derivative of any of the foregoing. 
     
     
         15 . The compound of  claim 14 , wherein the substituent X is a peptide, or a derivative thereof. 
     
     
         16 . The compound of  claim 14 , wherein the peptide is the transduction domain of HIV-1TAT protein, a Centyrin, a constrained peptide, a pHLIP peptide, or derivatives thereof. 
     
     
         17 . The compound of  claim 14 , wherein the substituent X is an antibody or antibody fragment, or a derivative thereof. 
     
     
         18 . The compound of  claim 17 , wherein the antibody fragment is a single-chain variable fragment, or derivative thereof. 
     
     
         19 . The compound of  claim 14 , wherein the substituent X is a carbohydrate, or a derivative thereof. 
     
     
         20 . The compound of  claim 14 , wherein the substituent X is a fatty acid, or a derivative thereof. 
     
     
         21 . The compound of  claim 14 , wherein the substituent X is a vitamin, or a derivative thereof. 
     
     
         22 . The compound of  claim 21 , wherein the substituent X is tocopherol or folate, or a derivative thereof. 
     
     
         23 . The compound of  claim 14 , wherein the substituent X is a cholesterol, or a derivative thereof. 
     
     
         24 . The compound of  claim 14 , wherein the substituent X is (2S,2′S)-2,2′-(Carbonyldiimino)dipentanedioic acid (DUPA), or a derivative thereof. 
     
     
         25 . The compound of  claim 14 , wherein the substituent X is anisamide, or a derivative thereof. 
     
     
         26 . The compound of  claim 14 , wherein the substituent X is an organometallic compound, or a derivative thereof. 
     
     
         27 . The compound of  claim 26 , wherein the organometallic compound is ferrocene, or a derivative thereof. 
     
     
         28 . The compound of  claim 14 , wherein substituent X is a small molecule, or a derivative thereof. 
     
     
         29 . The compound of  claim 28 , wherein the small molecule is lenalidomide, or a derivative thereof. 
     
     
         30 . The compound of  claim 2 , where in the compound is at least 80, 85, 90, 95, 96, 97, 98, 99, or 100% pure. 
     
     
         31 - 109 . (canceled)